Rod and cone photoreceptors degenerate under a variety of pathological conditions, including a wide array of hereditary retinal diseases, such as but not limited to, retinitis pigmentosa, macular degeneration, and cone-rod dystrophies. Defects in a large number of genes are linked to inherited retinal degenerative disorders, including but not limited to, those encoding enzymes involved in the recycling of 11-cis retinal in the retinal pigment epithelium (RPE), retinoid isomerase (RPE65) and lecithin retinol acyltransferase (LRAT), and the phototransduction-associated proteins (opsins, subunits of transducin, cGMP phosphodiesterase PDE6, guanylate cyclase, and the cyclic nucleotide-gated channel). There are currently no effective treatments for human retinal dystrophies. Despite a high genetic heterogeneity, the degenerating photoreceptors show common cellular disorder features, including but not limited to, oxidative damage, endoplasmic reticulum stress, and apoptosis.
Thyroid hormone (TH) signaling regulates cell proliferation, differentiation, and apoptosis. The role of TH signaling in the retina regarding its regulation of cone opsin expression and patterning has been well documented. Most mammals possess dichromatic color vision that is mediated by two opsins with peak sensitivities to medium-long (M, green) and short (S, blue) wavelengths of light. In the mouse, M- and S-opsins are expressed in opposing gradients such that varying amounts of both opsins are co-expressed in cones in mid-retinal regions, whereas M-opsin predominates in dorsal (superior) regions, and S-opsin predominates in ventral (inferior) regions (FIG. 1). During development and in the adult postmitotic retina, TH signaling via its receptor type β2 (TRβ2) suppresses expression of S-opsin, induces expression of M-opsin, and promotes the dorsal-ventral opsin patterning. Importantly, TH signaling has been associated with cone viability. Triiodothyronine (T3) treatment was shown to cause cone death in mice and this effect was reversed by deletion of TRβ2 gene. Excessive TH signaling was also shown to induce auditory defects and cochlear degeneration in mice. TH signaling has been associated with apoptosis of a variety of human cell lines, including but not limited to lymphocytes, breast cancer cells, HeLa cells, and pituitary tumor cells; TH signaling has also been well documented in apoptotic tissue remodeling during anuran metamorphosis.
As stated herein above, while it is known that photoreceptors degenerate in a wide array of hereditary retinal diseases, there is currently no treatment available for these retinal degenerations. Thus, there is a great need in the art for new compositions and methods for treating and/or inhibiting pathologic ocular conditions.